The long-term goal of the PI is to better understand the mechanisms that regulate the autonomic responses during exercise in normal subjects and patients with heart failure (HF). It is known that sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF patients at rest and in response to exercise. The muscle metaboreceptor contribution to regulation of muscle SNA is blunted in HF whereas the mechanoreceptor contribution is augmented. The underlying mechanisms will be explored in this proposal. The proposed experiments are based on recently published studies from our laboratory as well as pilot data that have been gathered. Specific aim #1 is designed to examine the role the vanilloid receptor subtype 1 (VR1) plays in evoking the muscle pressor reflex. Our data suggests that stimulation of VR1 by administration of capsaicin into the hindlimb muscle elevates blood pressure. We anticipate that VR1 induced-reflexive responses will be greater as the muscle interstitium is acidic. We further hypothetize that cardiovascular responses to muscle contraction will be attenuated by VR1 blockade. We will also examine what specific metabolites evoke an effect via activation of VR1. We anticipate that a VR1 receptor antagonist capsazepine will attenuate the pressor response induced by elevated muscle temperature but will not attenuate that by HVphosphate. However, a blocker of acid sensing ion channel (ASIC) amiloride will attenuate H+/phosphate-induced responses. In specific aim #2, cardiovascular responses to the metabolic stimulation in normal and HF (myocardial infarct) rats will be examined. We anticipate that the responses to VR1 stimulation, H+, phosphate and heat will be smaller in HF rats than in control rats. We hypothesize that in HF muscle temperature is lower and/or afferent nerve VR1 expression is attenuated in HF. In specific aim #3, the role ATP stimulation of P2X receptors plays in evoking the muscle reflex will be determined. We will further examine the role of muscle temperature in ATP-induced responses. We anticipate that the response will be greater at a lower mgscle temperature. In specific aim #4, cardiovascular responses to P2X stimulation in HF rats and control rats will be examined. We anticipate that the response to P2X stimulation will be larger in HF rats than in control rats. We hypothesize that muscle mechanoreflex is enhanced in HF is due to an increase in interstitial ATP concentration within exercising muscle and/or an elevation of P2X receptor expression in afferent nerves. Our pilot work suggests that activation of P2X receptors enhances the cardiovascular responses to stimulation of muscle mechanoreceptors and ATPi at rest is higher in HF rats than in controls. To accomplish these goals we will employ a decerebrate rat model to study the muscle reflex in the well-characterized rat coronary artery ligation model of congestive HF. To the best of our knowledge, experiments such as these have never been performed in an HF model. Completion of these studies in this proposal will provide a systematic evaluation of circulatory regulation during exercise in an important cardiovascular disease.